Alzheimer's Disease (AD) is a severe mental health problem that affects an estimated 3-4 million people in the United States (Keefover, 1996, Neurol. Clin. 14:337-351). Many studies have established that AD appears in two distinct forms: an early-onset form and a late-onset, sporadic form. Incidence of the latter form increases with age, and AD is now believed to be the most important single cause of senile dementia in humans. Estimates of the prevalence of late-onset AD based on epidemiological evidence vary, and the incidence of the disease appears to differ with the population examined. However, at least half of the total cases of dementia in the elderly may be attributable to AD (Evans et al., 1989, J. Amer. Med. Assn. 262:2551-2556; Breteler et al., 1992, Epidemiol. Rev. 14:59-82). Thus, AD is a significant mental health concern, which is likely to increase in importance with the continued aging of the population.
The signature neuropathology seen in essentially all AD patients includes the presence in the brain of neurofibrillary tangles (NFT) and neuropil threads (NT) comprised of modified tau protein, and the presence of neuritic senile plaques (NSP) comprised of deposits of β-amyloid peptide (Aβ). The genesis of these neuropathologies is poorly understood. Tau protein is a normal component of the neuronal cytoskeleton, and evidence suggests that the abnormal deposition of this protein in NFT, NT, and dystrophic neurites results from aberrant post-translational modification of the protein (Lee et al., 1991, Science 251:675-679; Alonso et al., 1996, Nature Med. 2:783-787; Appelt et al., 1996, J. Histochem. Cytochem. 44:1421-1427; Wang et al., 1996, Nature Med. 2:871-875). It is not clear whether NFT represent primary lesions in AD, or whether the formation of these structures is a response to other neuronal injuries associated with the disease (Goedert, 1993, Trends Neurosci. 16:460-465). Some reports suggest that the level of NFT accumulation correlates most closely with the degree of cognitive impairment in AD patients (McKee et al., 1991, Ann. Neurol. 30:156-165).
Deposition of Aβ appears to be critical in the neuronal degeneration observed in AD (Schellenberg, 1995, Proc. Natl. Acad. Sci. USA 92:8552-8559). In the early-onset, familial form of AD (FAD), mutations in the amyloid precursor protein gene are associated with increased Aβ deposition and early onset of symptoms (Yankner, 1996, Nature Med. 2:850-852). Mutations in the genes encoding presenilin-1 (PS-1) and presenilin-2 (PS-2) also lead to increased Aβ deposition in FAD human patients and in an animal model system (Lemere et al., 1996, Nature Med. 2:1146-1150; Yankner, supra). Mutations in PS-1 and PS-2 and mutations in βAPP appear to account for most early-onset, FAD cases (Lee et al., 1996, J. Neurosci. 16:7513-7525; Cook et al., 1996, Proc. Natl. Acad. Sci. USA 93:9223-9228).
Late-onset AD is more prevalent than early onset FAD. While early-onset FAD is almost certainly genetically-based, no such correlation has been established for late-onset AD. One risk factor identified in late-onset AD disease is the presence of the apolipoprotein E ε4 (APOE ε4) allele (Schellenberg, supra; Roses, 1996, Ann. Rev. Med. 47:387-400). Not all patients expressing the APOE ε4 allele develop AD. However, the presence of this allele is associated with increased risk for the disease by several-fold and the allele is also associated with earlier onset/more rapid progression in FAD (Roses, supra; Corder et al., 1993, Science 261-921-923). A recent study suggests that expression of the APOE ε4 allele may be a risk factor primarily in individuals younger than 70 years in age, and that it may be involved in only a minority of late-onset AD cases (Blacker et al., 1997, Neurol. 48:139-147).
The neuropathology characteristic of both early- and late-onset AD is similar, but the factors which initiate the pathology of late-onset AD remain to be elucidated (Clark et al., 1993, Arch. Neurol. 50:1164-1172; Lippa et al., 1996, Neurol. 46:406-412). Neurologic disease may be caused by microorganisms, and infection with agents that do not target the nervous system directly may elicit neuropathologic side-effects (Bolton et al., 1993, Ann. Neurol. 33:94-100; Johnson, 1994, J. Neurol. Sci. 124:3-14). In view of these reports, several groups have attempted to establish a causal relationship between viral infection and sporadic AD, but no etiologic link between the two has been unequivocally demonstrated. For example, measles virus, various lentiviruses, adenovirus and other infectious agents have been dismissed as potential agents associated with late-onset AD (e.g., Mann et al., 1983, Acta Neurol. 60:24-28; Friedlan et al., Arch. Neurol. 47:177-178; Pogo et al., 1987, Brain 110:907-915). Various bacterial species have also been evaluated and dismissed as potential agents associated with late-onset AD, including Chlamydia psittaci and Coxiella burnettii (e.g., Renvoize et al., 1987, Age and Ageing 16:311-314). One study identified herpes simplex virus type 1 (HSV-1) infection as a risk factor for development of AD in people expressing the APOE ε4 allele (Itzhaki et al., 1997, Lancet 349:241-244), although it is not clear how and under what circumstances this virus might interact with the allele or its gene product to produce or promote disease. In addition to viruses and bacteria, unconventional agents (i.e., prions) have been considered but have been dismissed as agents in the pathogenesis of AD (Mathews, 1986, Neuropath. Appl. Neurobiol. 12:11-116; Wisniewski et al., 1988, Ciba Fdn. Sympos. 135:224-238). The possible roles of other factors, including diet and extended/acute exposure to aluminum, have also been investigated, but no definitive role for these factors in the etiology of AD has been demonstrated (Keefover et al., supra; Gautrin et al., 1989, Can. J. Neurol. Sci. 16:375-387).
Chlamydia pneumoniae (C. pneumoniae) is an intracellular bacterium that is a respiratory pathogen, initially infecting the oral and nasal mucosa of humans (Grayston et al., 1990, J. Infect. Dis. 161:618-625). This organism is a significant agent in acute respiratory infections of humans, including pneumonia, sinusitis, and bronchitis (Grayston et al., 1990, supra; Grayston, 1992, Ann. Rev. Med. 43:317-323). Recent studies have also implicated C. pneumoniae in more severe and chronic pulmonary pathologies, including sarcoidosis and chronic obstructive pulmonary disease (Hahn et al., 1991, J. Amer. Med. Assn. 266:225-230; Grayston et al., 1993, J. Infec. Dis. 168:1231-1235). In addition, C. pneumoniae infection has been associated with multiple sclerosis and with meningoencephalitis (Sriram et al., 1998, Neurol. 50:571-572; Koskiniemi et al., 1996, Eur. Neurol. 36:160-163). Epidemiologic analyses have demonstrated that the prevalence of infection with C. pneumoniae is high in all adult populations studied, and that this prevalence increases with increasing age (Grayston, 1992, supra; Leinonen, 1993, Eur. Heart J. 14:57-61). In the Western world where population densities are relatively low, children under the age of 5 to 10 years rarely have anti-C. pneumoniae antibodies, but the incidence of the presence of antibodies rises sharply in these populations after the age of 10 (Grayston, 1992, supra; Leinonen, supra). C. pneumoniae antibody titers peak in the 6th-7th decades in most populations studied. For example, males 60 years and older in Seattle have a C. pneumoniae antibody prevalence rate of 70% (Grayston, 1992, supra; Leinonen, supra). All of the studies conducted to date indicate that virtually everyone is infected with C. pneumoniae during his or her lifetime, and that reinfection is common (Leinonen, supra).
Infection with C. pneumoniae has been implicated in unexpected clinical manifestations, including central nervous system disease and atherosclerosis (Gran et al., 1993, Scand. J. Rheumatol. 22:43-44; Campbell et al., 1995, J. Infect. Dis. 172:585-588; Koskiniemi et al., 1996, Eur. Neurol. 36:160-163; Muhlestein et al., 1996, J. Amer. Coll. Cardiol. 27:1555-1561). A correlation between central nervous system disease, primarily encephalitis, and serologically confirmed infection with C. pneumoniae has been found (Koskiniemi et al., supra). A significant correlation between serum anti-C. pneumoniae antibody titers and coronary artery disease has been established and the bacterium has been identified by electron microscopy and other methods in atheromatous plaques (Muhlestein et al., supra; Capron, 1996, Nature Med. 2:856-857). A significant correlation between serum anti-C. pneumoniae antibody titers and cerebrovascular disease has also been established (Wimmer et al., 1996, Stroke 27:2207-2210). A recent report postulated a relationship among atherosclerosis, APOE ε4 expression, and late-onset AD (Hofman et al., 1997, Lancet 349:151-153). A direct correlation between C. pneumoniae infection and AD has not been suggested.
Alzheimer's disease is a significant health concern and it is likely to increase in importance with the continued aging of the population. Effective methods for the treatment or prevention of AD are not currently available and there is a long felt need for such methods of treatment or prevention.